Abstract |
P-glycoprotein transporters (P-gp) located at the blood-brain barrier (BBB) are likely to play a role in refractory epilepsy. In vitro studies already pointed out that several antiepileptic drugs (AEDs) are substrate of P-gp. This study proposes a new in vivo approach to investigate the interaction between some AEDs and P-gp located at the BBB. (11)C-desmethylloperamide ((11)C-dLop), a radiolabelled substrate of P-gp, was intravenously administrated after pretreatment with saline or AEDs ( sodium valproate, levetiracetam, topiramate and phenytoin) at their human therapeutic and four times their therapeutic dose. The effect of the different pretreatment on the intracerebral concentration of (11)C-dLop was determined to indirectly investigate possible in vivo interactions between AEDs and P-gp. Pretreatment with levetiracetam, topiramate and phenytoin at therapeutic doses significantly decreased intracerebral concentration of (11)C-dLop. Pretreatment with a therapeutic dose of sodium valproate did not influence brain uptake of (11)C-dLop. In case of pretreatment with supratherapeutic doses of AED, (11)C-dLop brain uptake was not different compared to pretreatment with saline. The metabolisation rate of (11)C-dLop in plasma was unaltered, indicating that observed differences in brain uptake of the tracer were not due to pharmacokinetic changes. The following conclusion can be made: levetiracetam, topiramate and phenytoin demonstrate biphasic modulation of the BBB P-gp. At therapeutic doses they act as inducers of efflux, at supratherapeutic doses they have no effect on the efflux rate. Sodium valproate does not interact with P-gp at therapeutic nor at higher doses.
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Authors | Lieselotte Moerman, Leonie Wyffels, Dominique Slaets, Robrecht Raedt, Paul Boon, Filip De Vos |
Journal | Epilepsy research
(Epilepsy Res)
Vol. 94
Issue 1-2
Pg. 18-25
(Mar 2011)
ISSN: 1872-6844 [Electronic] Netherlands |
PMID | 21277169
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier B.V. All rights reserved. |
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B
- Anticonvulsants
- Carbon Isotopes
- N-demethylloperamide
- Loperamide
- multidrug resistance protein 3
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Topics |
- ATP Binding Cassette Transporter, Subfamily B
(deficiency, metabolism)
- Analysis of Variance
- Animals
- Anticonvulsants
(blood, pharmacology)
- Blood-Brain Barrier
(drug effects, metabolism)
- Brain
(diagnostic imaging, drug effects)
- Carbon Isotopes
(blood, metabolism, pharmacokinetics)
- Dose-Response Relationship, Drug
- Drug Interactions
- Loperamide
(analogs & derivatives, blood, chemistry, metabolism, pharmacokinetics)
- Male
- Mice
- Mice, Knockout
- Radioligand Assay
- Radionuclide Imaging
- Time Factors
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